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Aminated derivative of homoharringtonine, preparation method therefor, and application thereof

a technology homoharringtonine derivatives, which is applied in the field of natural medicine and pharmaceutical chemistry, can solve the problems of unreported synthesis and application of aminated or amidated homoharringtonine derivatives

Inactive Publication Date: 2014-07-24
HANGZHOU BENSHENG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is related to new compounds and methods for their preparation and use as pharmaceutical compositions, particularly for the treatment of tumors. These compounds are aminated or amidated homoharringtonine derivatives, which can be prepared by a two-step reaction involving the hydrolysis of homoharringtonine to produce an acid homoharringtonine, followed by its condensation with an organic amine to produce the desired compound. The compounds have shown promising results in treating various types of tumors, particularly leukemia, multiple myeloma, lymphoma, and glioma. The invention also includes the use of these compounds in pharmaceutical compositions and methods of treating tumors.

Problems solved by technology

However, reports on the synthesis and application of aminated or amidated homoharringtonine derivatives have not yet been seen.

Method used

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  • Aminated derivative of homoharringtonine, preparation method therefor, and application thereof
  • Aminated derivative of homoharringtonine, preparation method therefor, and application thereof
  • Aminated derivative of homoharringtonine, preparation method therefor, and application thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

The Synthesis of Compound BS-HH-043

[0091]

wherein, X01-1: homoharringtonine acid; Zi: furan-2-ethylamine; HATU: 2-(7-azobenzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate; DIPEA: N,N-diisopropylethylamine.

[0092]Homoharringtonine is hydrolyzed according to the general scheme above. Afterwards, the acid resulted from the hydrolysis of homoharringtonine, as an intermediate, X01-1(106 mg, 0.2 mmol), and 2-aminomethylfuran (24 mg, 0.24 mmol) are dissolved in anhydrous DMF (2 mL). N,N-diisopropylethylamine (52 mg, 0.4 mmol) and 2-(7-azobenzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (114 mg, 0.3 mmol) are added and the mixture is stirred for 3 h under 30° C. Water (6 mL) is added under 5-10° C. and the mixture is extracted with ethyl acetate. The organic phase is washed with a saturated saline solution, dried and concentrated. The crude product is separated and purified with a silicagel column (DCM: methanol=10:1) to give BS-HH-043 (9 mg, 6%) as a colorless o...

example 2

Evaluation of the Aminated Homoharringtonine Derivatives of the Present Invention for Their Anti-Leukemia Activities

[0158](1) Experimental Materials

[0159]Leukemia cell lines: K562 / adr (drug-resistant, chronic myeloid leukemia, CML), NB4 (acute promyelocytic leukemia, AML), Kasumi-1 (acute myeloid leukemia M2 type, AML-M2), Jurkat (acute lymphoblastic leukemia, ALL), all of which are donated by Cancer Research Institute of Zhejiang University, China; and H9 (acute lymphoblastic leukemia, ALL), which is purchased from China Center for Type Culture Collection.

[0160]Reagents: The standard sample of homoharringtonine (HHT) is purchased from Taihua Natural Plant Pharmaceutical Co., Ltd., Shaanxi, China; and the homoharringtonine derivatives of the present invention.

[0161]Main apparatuses: a Thermo Scientific 3111 incubator and a Bio-Rad iMark microplate reader.

[0162](2) Experimental Method

[0163]Obtaining 6000 well-growing leukemia cells and inoculating them into wells of a 96-well cell cu...

example 3

Evaluation of the Aminated Homoharringtonine Derivatives of the Present Invention for Their Anti-Human Multiple Myeloma and Lymphoma Cell Activities

[0166](1) Experimental Materials

[0167]Multiple myeloma and lymphoma cell lines: RPMI8226 (multiple myeloma), purchased from Fuxiang Bio-tech Co. Ltd., Shanghai, China.

[0168]Reagents: the same as in Example 2.

[0169]Main apparatuses: a Thermo Scientific 3111 incubator and a Bio-Rad iMark microplate reader.

[0170](2) Experimental Method

[0171]Obtaining 6000 well-growing leukemia cells and inoculating them into wells of a 96-well cell culture plate. The culture medium is the 1640 cell culture medium containing 10% fetal bovine serum. After adding the homoharringtonine derivatives of different concentrations and mixing uniformly, placing the plate in a carbon dioxide cell incubator (5% CO2) at 37° C. and incubating for 72 hours. Then the viable cell concentration is determined by the MTT method. In this experiment, the cell viability in control...

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Abstract

The present invention belongs to the field of natural medicine and pharmaceutical chemistry and specifically relates to novel aminated homoharringtonine derivatives of formula (I) and a pharmaceutically acceptable salt thereof, to a process for the preparation of these compounds, compositions containing such compounds and their use in preparing antineoplastic medicaments.

Description

TECHNICAL FIELD[0001]The present invention belongs to the field of natural medicine and pharmaceutical chemistry, and relates to novel homoharringtonine derivatives, in particular aminated homoharringtonine derivatives, to a process for the preparation of these compounds, compositions containing such compounds and their use in preparing antineoplastic medicaments.BACKGROUND OF THE INVENTION[0002]Homoharringtonine (HHT), also known as O-3-[(2R)-2,6-dihydroxy-2-(2′-methoxy-2′-oxoethyl)-6-methylheptanoyl]cephalotaxine, is an alkaloid extracted and separated from Chinese herbal plants of Cephalotaxaceae family, in particular from cephatotaxus fortuneif or congeners thereof. Cephatotaxus genus plants of the Cephalotaxaceae family consist of 9 species, 8 of which are originated in China. Plants of this genus contain a plurality of alkaloids, in which harringtonine, homoharringtonine, isoharringtonine and deoxyharringtonine have been extracted, identified and extensively investigated [ZHON...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D493/16
CPCC07D493/16C07D491/20A61P35/00A61P35/02A61P35/04
Inventor RONG, FRANKXU, RONGZHENXIE, FUWENLAI, HONGXI
Owner HANGZHOU BENSHENG PHARMA
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